Guanidine derivatives for the treatment of hepatitis c

ABSTRACT

Compounds of Formula I, including pharmaceutically acceptable salts thereof, are set forth, in addition to compositions and methods of using these compounds. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the priority of U.S. provisional application Ser. No. 61/756,562 filed Jan. 25, 2013 which is herein incorporated by reference.

FIELD OF THE INVENTION

The invention relates to novel compounds of Formula I, including pharmaceutically acceptable salts thereof, which have activity against hepatitis C virus (HCV), and are useful in treating those infected with HCV. The invention also relates to compositions and methods of using these compounds.

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) chronically infects an estimated 170 million people worldwide, with 3 to 4 million infected individuals in the United States alone (Boyer, N. and Marcellin, P. J. Hepatology. 2000, 32:98-112; Alter, M. J., et al. Engl. J. Med. 1999, 341:556-562). Prior to the mid 1990s, transfusion with infected blood products was the main route of HCV transmission. Following the introduction of blood screening methods, transmission via injection drug use became the primary risk factor. Chronic infection often leads to the development of severe liver complications, including fibrosis, cirrhosis, and hepatocellular carcinoma. HCV infection is also the leading cause of orthotopic liver transplantation in the United States. The degree to which disease progression is related to viral and cellular factors is not completely understood.

Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence of the HCV genome (Simmonds, P. J. Gen. Virology. 2004, 85:3173-3188). Based on this sequence diversity, six major genotypes and multiple associated subtypes have been described. The genotypes of HCV differ in their worldwide distribution, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy.

Medical treatment for HCV is limited by the lack of a vaccine or approved therapies that specifically target the virus. Currently, patients undergo treatment with a combination of parenterally administered pegylated alpha-interferon and oral ribavirin. Genotype 1 HCV is the most difficult to treat and elimination of the virus (sustained virologic response) is achieved for only approximately 50% of patients (Fried, M. W. et al. N. Engl. J. Med. 2002, 347:975-982; Zeumzem, S. Nature Clinical Practice. 2008, 5:610-622). This poor treatment response, combined with often severe side effects induced by therapy, highlight a need for improved antiviral drugs with better efficacy and safety profiles.

HCV is a member of the Flaviviridae family of viruses with a single-stranded positive-sense RNA genome. Following infection of host cells, the 9.6 Kb genome is translated into a polyprotein precursor of approximately 3,000 amino acids (reviewed in Lindenbach, B. D. and Rice, C. M. Nature. 2005, 436:933-938; Moradpour, D, Penin, F., and Rice, C. M. Nature Reviews. 2007, 5:453-463). Post-translational processing by both cellular and viral proteases results in the generation of at least 10 separate viral proteins. The structural proteins (which by definition are found in mature virions) include core, E1, E2, and possibly p7, and originate from the amino-terminal region of the polyprotein. The core protein assembles into the viral nucleocapsid. The E1 and E2 glycoproteins form heterodimers that are found within the lipid envelope surrounding the viral particles, and mediate host cell receptor binding and entry of the virus into cells. It is unclear if p7 is a structural protein, and its role in replication has yet to be defined. However p7 is believed to form an ion channel in cellular membranes, preventing acidification of intracellular compartments in which virions are assembled, and it has been shown to be essential for viral replication and assembly. The nonstructural proteins NS2, NS3, NS4A, NS4B, NSSA, and NSSB are produced through maturational cleavages of the carboxy-terminal region of the polyprotein. NS2 along with the amino terminus of NS3 form the NS2-3 metalloprotease which cleaves at the NS2-NS3 junction. Additionally, NS2 is involved in assembly and egress of nascent virions. The NS3 protein contains both a serine protease in its amino-terminal region, and a nucleotide-dependent RNA helicase in its carboxy-terminal region. NS3 forms a heterodimer with the NS4A protein, constituting the active protease which mediates cleavages of the polyprotein downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. The NS4B protein has been shown to be important for localization of HCV proteins into replication complexes in altered membranous structures within the cell. NS5B encodes an RNA-dependent RNA polymerase that is involved in the replication of HCV.

Subgenomic HCV replicons, containing the untranslated regions 5′ and 3′ to the coding sequence fused to the nonstructural proteins or the full-length polyprotein, are competent for translation, viral protein expression, and replication within cultured cells (Lohmann, V. et al. Science. 1999, 285:110-113; Moradpour, D, Penin, F., and Rice, C. M. Nature Reviews. 2007, 5:453-463). The replicon system has proven valuable for the identification of inhibitors targeting the nonstructural proteins associated with these functions. However, only limited subsets of HCV genotypes have been used to generate functional replicons.

Other systems have been used to study the biology of the HCV structural proteins that mediate the entry into host cells. For example, virus-like-particles made in recombinant baculovirus-infected cells with the HCV core, E1 and E2 proteins have also been used to study the function of the HCV E1 and E2 proteins (Barth, H., et al. J. Biol. Chem. 2003, 278:41003-41012). In addition, pseudotyping systems where the E1 and E2 glycoproteins are used to functionally replace the glycoproteins of retroviruses have been developed (Bartosch, B., Dubuisson, J. and Cosset, F.-L. J. Exp. Med. 2003, 197:633-642; Hsu, M. et al. Proc. Natl. Acad. Sci. USA. 2003, 100:7271-7276). These systems yield HCV pseudoparticles that bind to and enter host cells in a manner which is believed to be analogous to the natural virus, thus making them a convenient tool to study the viral entry steps as well as to identify inhibitors block this process.

Recently, a full-length genotype 2a HCV clone, JFH1, was isolated and demonstrated the ability to replicate in vitro. Through repeated passage and adaptation in cell culture increased titers of infectious virus were produced (Lindenbach, B. D., et al. Science. 2005, 309:623-626; Wakita, T. et al. Nature Med. 2005, 11:791-796). In contrast to the HCV replicon or pseudotyping systems, the infectious virus is useful for studying the complete HCV replication cycle, including identifying inhibitors of not only the replication proteins, but those involved in early steps in virus infection (entry and uncoating) and production of progeny viruses (genome packaging, nucleocapsid assembly, virion envelopment and egress).

Triazines have been disclosed. See WO 2009/091388 and US 2009/0286778.

The invention provides technical advantages, for example, the compounds are novel and are effective against hepatitis C. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.

SUMMARY OF THE INVENTION

One aspect of the invention is a compound of Formula I, including pharmaceutically acceptable salts thereof:

wherein

-   a, b and c are each nitrogen; -   or a and b are each nitrogen, while c is —CH; -   or b and c are each nitrogen, while a is —CH; -   or a and c are each nitrogen, while b is —CH; -   R¹ is selected from alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,     cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl,     cycloalkenyl, indanyl, alkylcarbonyl, and benzyl, wherein the benzyl     moiety is substituted with 0-3 substituents selected from halo,     alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, cyano, haloalkyl,     alkoxy, and haloalkoxy; -   R² is selected from alkyl, cycloalkyl, ((Ar¹)alkyl, (Ar¹)cycloalkyl,     ((Ar¹)cycloalkyl)alkyl, ((Ar¹)alkyl)cycloalkyl, and     (((Ar¹)alkyl)cycloalkyl)alkyl; -   Ar¹ is phenyl substituted with 0-3 substituents selected from halo,     hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl,     alkoxy, and haloalkoxy; -   R³ is hydrogen, alkyl or cycloalkyl; -   R⁴ is selected from hydrogen, halogen, alkyl, alkoxyl, alkylamino     and alkylthio; -   or R² and R⁴ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   Y is

-   X is selected from O, NR¹¹, CO, CONR¹¹, NR¹¹NR¹² and CONR¹¹NR¹²; -   R¹¹ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,     haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl,     halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, and benzyl,     wherein the benzyl moiety is substituted with 0-3 substituents     selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; -   R¹² is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,     haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl,     halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, and benzyl,     wherein the benzyl moiety is substituted with 0-3 substituents     selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; -   R⁵ is selected from alkyl, cycloalkyl, (cycloalkyl)alkyl,     (alkyl)cycloalkyl, ((alkyl))cycloalkyl)alkyl, a bridged     bicycloalkyl, a fused bicycloalkyl, and a spiro bicycloalkyl, and is     substituted with 0-4 substituents selected from the group of halo,     alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy,     benzyloxy, CO₂R¹³, CON(R¹⁴)(R¹⁵), N(R¹⁴)(R¹⁵), tetrahydrofuranyl,     tetrahydropyranyl, and Ar²; -   or R⁵ is Ar³; -   R¹³ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,     ((hydroxyalkyl)alkoxy)alkoxy, and ((alkoxy)alkoxy)alkoxy; -   R¹⁴ is selected from hydrogen, alkyl, cycloalkyl, alkylcarbonyl, and     alkoxycarbonyl, which is substituted with 0-4 substituents selected     from the group of halo, alkyl, cycloalkyl, hydroxyalkyl,     alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO₂R²¹, CON(R²²)(R²³), and     N(R²²)(R²³); -   R¹⁵ is hydrogen or alkyl; -   or R¹⁴ and R¹⁵ taken together with the nitrogen to which they are     attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or     morpholinyl, and is substituted with 0-2 substituents selected from     alkyl, alkylcarbonyl, and alkoxycarbonyl; -   R²¹ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,     ((hydroxyalkyl)alkoxy)alkoxy, and ((alkoxy)alkoxy)alkoxy; -   R²² is selected from hydrogen, alkyl, cycloalkyl, alkylcarbonyl, and     alkoxycarbonyl, which is substituted with 0-4 substituents selected     from the group of halo, alkyl, cycloalkyl, hydroxyalkyl,     alkoxyalkyl, hydroxy, alkoxy, benzyloxy, ester, amido, and amino; -   R²³ is hydrogen or alkyl; -   or R²² and R²³ taken together with the nitrogen to which they are     attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or     morpholinyl, and is substituted with 0-2 substituents selected from     alkyl, alkylcarbonyl, and alkoxycarbonyl; -   Ar² is selected from phenyl, indanyl, tetrahydronaphthyl,     isochromanyl, benzodioxolyl, pyridinyl, pyrazolyl, imidazolyl, and     triazolyl, and is substituted with 0-3 substituents selected from     cyano, halo, alkyl, alkyenyl, haloalkyl, alkoxy, haloalkoxy,     N(R¹⁶)(R¹⁷), and alkylCO; -   R¹⁶ is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, or     alkoxycarbonyl; -   R¹⁷ is hydrogen or alkyl; -   or R¹⁶ and R¹⁷ taken together with the nitrogen to which they are     attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or     morpholinyl, and is substituted with 0-2 substituents selected from     alkyl, alkylcarbonyl, and alkoxycarbonyl; -   Ar³ is selected from phenyl, indanyl, fluorenyl, biphenyl,     terphenyl, pyridinyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl,     triazolyl, benzoxazolyl, indolinyl, and dibenzofuranyl, and is     substituted with 0-3 substituents selected from cyano, halo, alkyl,     alkenyl, haloalkyl, cycloalkyl, (CO₂R¹³)alkyl, (CO₂R¹³)alkenyl,     (CON(R¹⁶)(R¹⁷))alkyl, phenyl, hydroxyl, alkoxy, haloalkoxy,     alkylcarbonyl, CO₂R¹³, CON(R¹⁶)(R¹⁷), and PhCONHSO₂; -   or Ar³ is phenyl substituted with 1 substituent selected from     benzyl, tetrazolyloxy, thiazolyl, phenylpyrazolyl,     methyloxadiazolyl, thiadiazolyl, triazolyl, methyltriazolyl,     tetrazolyl, pyridinyl, and dimethoxypyrimdinyl; -   R⁶ is hydrogen, alkyl, cycloalkyl, CN or CON(R¹⁶)(R¹⁷); -   R⁷ is hydrogen, alkyl, cycloalkyl, CN or CON(R¹⁶)(R¹⁷); -   R⁸ is hydrogen, alkyl, cycloalkyl, CN or CON(R¹⁶)(R¹⁷); -   R⁹ is hydrogen, alkyl, cycloalkyl, CN or CON(R¹⁶)(R¹⁷);

or R⁶ and R⁷ can be connected by a carbon, oxygen, nitrogen or sulfur atom to form a ring;

-   or R⁶ and R⁸ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   or R⁷ and R⁸ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   or R⁸ and R⁹ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   or R⁶ and R¹¹ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   or R⁷ and R¹¹ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   or R⁸ and R¹¹ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring.

The invention also relates to pharmaceutical compositions comprising a compound of Formula 1, including a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In addition, the invention provides one or more methods of treating hepatitis C infection comprising administering a therapeutically effective amount of a compound of Formula I to a patient.

Also provided as part of the invention are one or more methods for making the compounds of Formula I.

The present invention is directed to these, as well as other important ends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Unless otherwise specifically set forth elsewhere in the application, these terms shall have the following meanings. “H” refers to hydrogen, including its isotopes, such as deuterium. “Halo” means fluoro, chloro, bromo, or iodo. “Alkyl” means a straight or branched alkyl group composed of 1 to 6 carbons. “Alkenyl” means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. “Cycloalkyl” means a monocyclic ring system composed of 3 to 8 carbons. “Alkylene” means a straight or branched divalent alkyl group. “Alkenylene” means a straight or branched divalent alkyl group with at least one double bond. “Cycloalkylene” means a divalent cycloalkane moiety composed of 3 to 7 carbons and includes gem-divalency (for example 1,1-cyclopropanediyl) as well as non-gem-divalency (for example, 1,4-cyclohexanediyl). “Alkylidinyl” means a divalent alkene substituent where the divalency occurs on the same carbon of the alkene. “Hydroxyalkyl,” “alkoxy” and other terms with a substituted alkyl moiety include straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety. “Haloalkyl” and “haloalkoxy” include all halogenated isomers from monohalo substituted alkyl to perhalo substituted alkyl. “Aryl” includes carbocyclic and heterocyclic aromatic substituents. Phenylene is a divalent benzene ring. “1,4-Phenylene” means 1,4-benzenediyl with respect to regiochemistry for the divalent moiety. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.

The substituents described above may be attached at any suitable point of attachment unless otherwise specified. However, it is understood that the compounds encompassed by the present invention are those that are chemically stable as understood by those skilled in the art. Additionally, the compounds encompassed by the present disclosure are those that are suitably stable for use as a pharmaceutical agent.

As set forth above, the invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, camsylate, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention possess asymmetric carbon atoms (see, for example, the structures below). The invention includes all stereoisomeric forms, including enantiomers and diastereomers as well as mixtures of stereoisomers such as racemates. Some stereoisomers can be made using methods known in the art. Stereoisomeric mixtures of the compounds and related intermediates can be separated into individual isomers according to methods commonly known in the art. The use of wedges or hashes in the depictions of molecular structures in the following schemes and tables is intended only to indicate relative stereochemistry, and should not be interpreted as implying absolute stereochemical assignments.

The invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

As set forth above, the invention is directed to compounds of Formula I, including pharmaceutically acceptable salts thereof:

wherein

-   a, b and c are each nitrogen; -   or a and b are each nitrogen, while c is —CH; -   or b and c are each nitrogen, while a is —CH; -   or a and c are each nitrogen, while b is —CH; -   R¹ is selected from alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,     cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl,     cycloalkenyl, indanyl, alkylcarbonyl, and benzyl, wherein the benzyl     moiety is substituted with 0-3 substituents selected from halo,     alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, cyano, haloalkyl,     alkoxy, and haloalkoxy; -   R² is selected from alkyl, cycloalkyl, ((Ar¹)alkyl, (Ar¹)cycloalkyl,     ((Ar¹)cycloalkyl)alkyl, ((Ar¹)alkyl)cycloalkyl, and     (((Ar¹)alkyl)cycloalkyl)alkyl; -   Ar¹ is phenyl substituted with 0-3 substituents selected from halo,     hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl,     alkoxy, and haloalkoxy; -   R³ is hydrogen, alkyl or cycloalkyl; -   R⁴ is selected from hydrogen, halogen, alkyl, alkoxyl, alkylamino     and alkylthio; -   or R² and R⁴ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   Y is

-   X is selected from O, NR¹¹, CO, CONR¹¹, NR¹¹NR¹² and CONR¹¹NR¹²; -   R¹¹ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,     haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl,     halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, and benzyl,     wherein the benzyl moiety is substituted with 0-3 substituents     selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; -   R¹² is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,     haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl,     halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, and benzyl,     wherein the benzyl moiety is substituted with 0-3 substituents     selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; -   R⁵ is selected from alkyl, cycloalkyl, (cycloalkyl)alkyl,     (alkyl)cycloalkyl, ((alkyl))cycloalkyl)alkyl, a bridged     bicycloalkyl, a fused bicycloalkyl, and a spiro bicycloalkyl, and is     substituted with 0-4 substituents selected from the group of halo,     alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy,     benzyloxy, CO₂R¹³, CON(R¹⁴)(R¹⁵), N(R¹⁴)(R¹⁵), tetrahydrofuranyl,     tetrahydropyranyl, and Ar²; -   or R⁵ is Ar³; -   R¹³ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,     ((hydroxyalkyl)alkoxy)alkoxy, and ((alkoxy)alkoxy)alkoxy; -   R¹⁴ is selected from hydrogen, alkyl, cycloalkyl, alkylcarbonyl, and     alkoxycarbonyl, which is substituted with 0-4 substituents selected     from the group of halo, alkyl, cycloalkyl, hydroxyalkyl,     alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO₂R²¹, CON(R²²)(R²³), and     N(R²²)(R²³); -   R¹⁵ is hydrogen or alkyl; -   or R¹⁴ and R¹⁵ taken together with the nitrogen to which they are     attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or     morpholinyl, and is substituted with 0-2 substituents selected from     alkyl, alkylcarbonyl, and alkoxycarbonyl; -   R²¹ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,     ((hydroxyalkyl)alkoxy)alkoxy, and ((alkoxy)alkoxy)alkoxy; -   R²² is selected from hydrogen, alkyl, cycloalkyl, alkylcarbonyl, and     alkoxycarbonyl, which is substituted with 0-4 substituents selected     from the group of halo, alkyl, cycloalkyl, hydroxyalkyl,     alkoxyalkyl, hydroxy, alkoxy, benzyloxy, ester, amido, and amino; -   R²³ is hydrogen or alkyl; -   or R²² and R²³ taken together with the nitrogen to which they are     attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or     morpholinyl, and is substituted with 0-2 substituents selected from     alkyl, alkylcarbonyl, and alkoxycarbonyl; -   Ar² is selected from phenyl, indanyl, tetrahydronaphthyl,     isochromanyl, benzodioxolyl, pyridinyl, pyrazolyl, imidazolyl, and     triazolyl, and is substituted with 0-3 substituents selected from     cyano, halo, alkyl, alkyenyl, haloalkyl, alkoxy, haloalkoxy,     N(R¹⁶)(R¹⁷), and alkylCO; -   R¹⁶ is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, or     alkoxycarbonyl; -   R¹⁷ is hydrogen or alkyl; -   or R¹⁶ and R¹⁷ taken together with the nitrogen to which they are     attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or     morpholinyl, and is substituted with 0-2 substituents selected from     alkyl, alkylcarbonyl, and alkoxycarbonyl; -   Ar³ is selected from phenyl, indanyl, fluorenyl, biphenyl,     terphenyl, pyridinyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl,     triazolyl, benzoxazolyl, indolinyl, and dibenzofuranyl, and is     substituted with 0-3 substituents selected from cyano, halo, alkyl,     alkenyl, haloalkyl, cycloalkyl, (CO₂R¹³)alkyl, (CO₂R¹³)alkenyl,     (CON(R¹⁶)(R¹⁷))alkyl, phenyl, hydroxyl, alkoxy, haloalkoxy,     alkylcarbonyl, CO₂R¹³, CON(R¹⁶)(R¹⁷), and PhCONHSO₂; -   or Ar³ is phenyl substituted with 1 substituent selected from     benzyl, tetrazolyloxy, thiazolyl, phenylpyrazolyl,     methyloxadiazolyl, thiadiazolyl, triazolyl, methyltriazolyl,     tetrazolyl, pyridinyl, and dimethoxypyrimdinyl; -   R⁶ is hydrogen, alkyl, cycloalkyl, CN or CON(R¹⁶)(R¹⁷); -   R⁷ is hydrogen, alkyl, cycloalkyl, CN or CON(R¹⁶)(R¹⁷); -   R⁸ is hydrogen, alkyl, cycloalkyl, CN or CON(R¹⁶)(R¹⁷); -   R⁹ is hydrogen, alkyl, cycloalkyl, CN or CON(R¹⁶)(R¹⁷); -   or R⁶ and R⁷ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   or R⁶ and R⁸ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   or R⁷ and R⁸ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   or R⁸ and R⁹ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   or R⁶ and R¹¹ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   or R⁷ and R¹¹ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring; -   or R⁸ and R¹¹ can be connected by a carbon, oxygen, nitrogen or     sulfur atom to form a ring.

More preferred compounds, including pharmaceutically acceptable salts thereof, are selected from the group of

In addition, other preferred compounds, including pharmaceutically acceptable salts thereof, are selected from the group of

Pharmaceutical Compositions and Methods of Treatment

The compounds demonstrate activity against HCV NS5B and can be useful in treating HCV and HCV infection. Therefore, another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a composition further comprising a compound having anti-HCV activity.

Another aspect of the invention is a composition where the compound having anti-HCV activity is an interferon or a ribavirin. Another aspect of the invention is where the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, interferon lambda, and lymphoblastoid interferon tau.

Another aspect of the invention is a composition where the compound having anti-HCV activity is a cyclosporin. Another aspect of the invention is where the cyclosporin is cyclosporin A.

Another aspect of the invention is a composition where the compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is a composition where the compound having anti-HCV activity is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, an interferon and ribavirin.

Another aspect of the invention is a method of inhibiting the function of the HCV replicon comprising contacting the HCV replicon with a compound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of inhibiting the function of the HCV NS5B protein comprising contacting the HCV NS5B protein with a compound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof. In another embodiment the compound is effective to inhibit the function of the HCV replicon. In another embodiment the compound is effective to inhibit the function of the HCV NS5B protein.

Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in conjunction with (prior to, after, or concurrently) another compound having anti-HCV activity.

Another aspect of the invention is the method where the other compound having anti-HCV activity is an interferon or a ribavirin.

Another aspect of the invention is the method where the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, interferon lambda, and lymphoblastoid interferon tau.

Another aspect of the invention is the method where the other compound having anti-HCV activity is a cyclosporin.

Another aspect of the invention is the method where the cyclosporin is cyclosporin A.

Another aspect of the invention is the method where the other compound having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of target in the HCV life cycle other than the HCV NS5B protein.

“Therapeutically effective” means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of hepatitis and HCV infection.

“Patient” means a person infected with the HCV virus and suitable for therapy as understood by practitioners in the field of hepatitis and HCV infection.

“Treatment,” “therapy,” “regimen,” “HCV infection,” and related terms are used as understood by practitioners in the field of hepatitis and HCV infection.

The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including for example capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th edition, 1985.

Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of about 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is about 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other agents used clinically. Typically, the daily dose will be about 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, will be determined by a physician using sound medical judgement.

The invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating hepatitis and HCV infection. In these combination methods, the compound will generally be given in a daily dose of about 1-100 mg/kg body weight daily in conjunction with other agents. The other agents generally will be given in the amounts used therapeutically. The specific dosing regime, however, will be determined by a physician using sound medical judgement.

Some examples of compounds suitable for compositions and methods are listed in Table 1.

TABLE 1 Physiological Type of Inhibitor or Brand Name Class Target Source Company NIM811 Cyclophilin Inhibitor Novartis Zadaxin Immuno-modulator Sciclone Suvus Methylene blue Bioenvision Actilon TLR9 agonist Coley (CPG10101) Batabulin (T67) Anticancer β-tubulin inhibitor Tularik Inc., South San Francisco, CA ISIS 14803 Antiviral antisense ISIS Pharmaceuticals Inc, Carlsbad, CA/Elan Phamaceuticals Inc., New York, NY Summetrel Antiviral antiviral Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA GS-9132 (ACH- Antiviral HCV Inhibitor Achillion/Gilead 806) Pyrazolopyrimidine Antiviral HCV Inhibitors Arrow Therapeutics compounds and salts Ltd. From WO-2005047288 26 May 2005 Levovirin Antiviral IMPDH inhibitor Ribapharm Inc., Costa Mesa, CA Merimepodib Antiviral IMPDH inhibitor Vertex (VX-497) Pharmaceuticals Inc., Cambridge, MA XTL-6865 (XTL- Antiviral monoclonal antibody XTL 002) Biopharmaceuticals Ltd., Rehovot, Isreal Telaprevir Antiviral NS3 serine protease Vertex (VX-950, LY- inhibitor Pharmaceuticals 570310) Inc., Cambridge, MA/Eli Lilly and Co. Inc., Indianapolis, IN HCV-796 Antiviral NS5B Replicase Wyeth/Viropharma Inhibitor NM-283 Antiviral NS5B Replicase Idenix/Novartis Inhibitor GL-59728 Antiviral NS5B Replicase Gene Labs/ Inhibitor Novartis GL-60667 Antiviral NS5B Replicase Gene Labs/ Inhibitor Novartis 2′C MeA Antiviral NS5B Replicase Gilead Inhibitor PSI 6130 Antiviral NS5B Replicase Roche Inhibitor R1626 Antiviral NS5B Replicase Roche Inhibitor 2′C Methyl Antiviral NS5B Replicase Merck adenosine Inhibitor JTK-003 Antiviral RdRp inhibitor Japan Tobacco Inc., Tokyo, Japan Levovirin Antiviral ribavirin ICN Pharmaceuticals, Costa Mesa, CA Ribavirin Antiviral ribavirin Schering-Plough Corporation, Kenilworth, NJ Viramidine Antiviral Ribavirin Prodrug Ribapharm Inc., Costa Mesa, CA Heptazyme Antiviral ribozyme Ribozyme Pharmaceuticals Inc., Boulder, CO BILN-2061 Antiviral serine protease Boehringer inhibitor Ingelheim Pharma KG, Ingelheim, Germany SCH 503034 Antiviral serine protease Schering Plough inhibitor Zadazim Immune modulator Immune modulator SciClone Pharmaceuticals Inc., San Mateo, CA Ceplene Immunomodulator immune modulator Maxim Pharmaceuticals Inc., San Diego, CA CellCept Immunosuppressant HCV IgG immuno- F. Hoffmann-La suppressant Roche LTD, Basel, Switzerland Civacir Immunosuppressant HCV IgG immuno- Nabi suppressant Biopharmaceuticals Inc., Boca Raton, FL Albuferon - α Interferon albumin IFN-α2b Human Genome Sciences Inc., Rockville, MD Infergen A Interferon IFN InterMune alfacon-1 Pharmaceuticals Inc., Brisbane, CA Omega IFN Interferon IFN-ω Intarcia Therapeutics IFN-β and Interferon IFN-β and EMZ701 Transition EMZ701 Therapeutics Inc., Ontario, Canada Rebif Interferon IFN-β1a Serono, Geneva, Switzerland Roferon A Interferon IFN-α2a F. Hoffmann-La Roche LTD, Basel, Switzerland Intron A Interferon IFN-α2b Schering-Plough Corporation, Kenilworth, NJ Intron A and Interferon IFN-α2b/α1-thymosin RegeneRx Zadaxin Biopharma. Inc., Bethesda, MD/ SciClone Pharmaceuticals Inc, San Mateo, CA Rebetron Interferon IFN-α2b/ribavirin Schering-Plough Corporation, Kenilworth, NJ Actimmune Interferon INF-γ InterMune Inc., Brisbane, CA Interferon-β Interferon Interferon-β-1a Serono Multiferon Interferon Long lasting IFN Viragen/ Valentis Wellferon Interferon Lympho-blastoid IFN- GlaxoSmithKline αn1 plc, Uxbridge, UK Omniferon Interferon natural IFN-α Viragen Inc., Plantation, FL Pegasys Interferon PEGylated IFN-α2a F. Hoffmann-La Roche LTD, Basel, Switzerland Pegasys and Interferon PEGylated IFN-α2a/ Maxim Ceplene immune modulator Pharmaceuticals Inc., San Diego, CA Pegasys and Interferon PEGylated IFN- F. Hoffmann-La Ribavirin α2a/ribavirin Roche LTD, Basel, Switzerland PEG-Intron Interferon PEGylated IFN-α2b Schering-Plough Corporation, Kenilworth, NJ PEG-Intron/ Interferon PEGylated IFN- Schering-Plough Ribavirin α2b/ribavirin Corporation, Kenilworth, NJ IP-501 Liver protection antifibrotic Indevus Pharmaceuticals Inc., Lexington, MA IDN-6556 Liver protection caspase inhibitor Idun Pharmaceuticals Inc., San Diego, CA ITMN-191 (R-7227) Antiviral serine protease InterMune inhibitor Pharmaceuticals Inc., Brisbane, CA GL-59728 Antiviral NS5B Replicase Genelabs Inhibitor ANA-971 Antiviral TLR-7 agonist Anadys Boceprevir Antiviral serine protease Schering Plough inhibitor TMS-435 Antiviral serine protease Tibotec BVBA, inhibitor Mechelen, Belgium BI-201335 Antiviral serine protease Boehringer inhibitor Ingelheim Pharma KG, Ingelheim, Germany MK-7009 Antiviral serine protease Merck inhibitor PF-00868554 Antiviral replicase inhibitor Pfizer ANA598 Antiviral Non-Nucleoside Anadys NS5B Polymerase Pharmaceuticals, Inhibitor Inc., San Diego, CA, USA IDX375 Antiviral Non-Nucleoside Idenix Replicase Inhibitor Pharmaceuticals, Cambridge, MA, USA BILB 1941 Antiviral NS5B Polymerase Boehringer Inhibitor Ingelheim Canada Ltd R&D, Laval, QC, Canada PSI-7851 Antiviral Nucleoside Pharmasset, Polymerase Inhibitor Princeton, NJ, USA PSI-7977 Antiviral Nucleotide NS5B Pharmasset, Polymerase Inhibitor Princeton, NJ, USA VCH-759 Antiviral NS5B Polymerase ViroChem Pharma Inhibitor VCH-916 Antiviral NS5B Polymerase ViroChem Pharma Inhibitor GS-9190 Antiviral NS5B Polymerase Gilead Inhibitor Peg-interferon Antiviral Interferon ZymoGenetics/ lamda Bristol-Myers Squibb

Synthetic Methods

The compounds may be made by methods available in the art, as well as those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. The variables (e.g. numbered “R” substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention.

Abbreviations used in the schemes generally follow conventions used in the art. Chemical abbreviations used in the specification and examples are defined as follows: “NaHMDS” for sodium bis(trimethylsilyl)amide; “DMF” for N,N-dimethylformamide; “MeOH” for methanol; “NBS” for N-bromosuccinimide; “Ar” for aryl; “TFA” for trifluoroacetic acid; “LAH” for lithium aluminum hydride; “BOC”, “DMSO” for dimethylsulfoxide; “h” for hours; “rt” for room temperature or retention time (context will dictate); “min” for minutes; “EtOAc” for ethyl acetate; “THF” for tetrahydrofuran; “EDTA” for ethylenediaminetetraacetic acid; “Et₂O” for diethyl ether; “DMAP” for 4-dimethylaminopyridine; “DCE” for 1,2-dichloroethane; “ACN” for acetonitrile; “DME” for 1,2-dimethoxyethane; “HOBt” for 1-hydroxybenzotriazole hydrate; “DIEA” for diisopropylethylamine, “Nf” for CF₃(CF₂)₃SO₂-; and “TMOF” for trimethylorthoformate.

Abbreviations are defined as follows: “1×” for once, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” for equivalent or equivalents, “g” for gram or grams, “mg” for milligram or milligrams, “L” for liter or liters, “mL” for milliliter or milliliters, “μL” for microliter or microliters, “N” for normal, “M” for molar, “mmol” for millimole or millimoles, “min” for minute or minutes, “h” for hour or hours, “rt” for room temperature, “RT” for retention time, “atm” for atmosphere, “psi” for pounds per square inch, “conc.” for concentrate, “sat” or “sat'd ” for saturated, “MW” for molecular weight, “mp” for melting point, “ee” for enantiomeric excess, “MS” or “Mass Spec” for mass spectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR” for high resolution, “HRMS” for high resolution mass spectrometry, “LCMS” for liquid chromatography mass spectrometry, “HPLC” for high pressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” for nuclear magnetic resonance spectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet, “d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designations familiar to one skilled in the art.

Chemistry Experimental LC/MS Method (i.e., Compound Identification)

All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10AS or LC-20AS liquid chromotograph using a SPD-10AV or SPD-20A UV-Vis detector and Mass Spectrometry (MS) data were determined with a Micromass Platform for LC in electrospray mode.

HPLC Method (i.e., Compound Isolation)

Compounds purified by preparative HPLC were diluted in methanol (1.2 mL) and purified using a Shimadzu LC-8A or LC-10A or Dionex APS-3000 or Waters Acquity™ automated preparative HPLC system.

Syntheses of Intermediates: Preparation of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid, In-01

Step 1: To a solution of 2,4,6-trichloro-1,3,5-triazine (15 g) in THF (300 mL) was added 2,2,2-trifluoroethanol (8.14 g) and Hunig'sBase (15.63 mL). The resulting mixture was stirred for 16 hours. After removal of most THF and precipitate through a plug washing with THF, the filtrate was concentrate to give a crude that will be used as it is.

Step 2: To a solution of the product in Step 1 above (10 g) in THF (100 mL) was added tert-butyl 4-aminobenzoate (7.79 g) and Hunig'sBase (7.04 mL). The resulting mixture was stirred for 16 h. The precipitate was filtered and washed with Et₂O, dried, then washed with water and dried to give 10.6 g of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate as a solid.

tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)- 1,3,5-triazin-2-ylamino)benzoate MS (M + H)⁺ Calcd. 405.1 MS (M + H)⁺ Observ. 405.0 LC Condition Solvent A 100% Water - 0.1% TFA Solvent B 100% ACN - 0.1% TFA Start % B 2 Final % B 98 Gradient Time 1.6 min Stop Time 1.8 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN -H₂0 - 0.1% TFA Column Aquity UPLC BEH C18 1.7 um

Step 3: To a slurry of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (3.6 g) and1-(4-chlorophenyl)cyclopropanamine (1.49 g) in THF (50 mL) was stirred for 5 hours at 80° C. The precipitate was filtrated through a plug washing with THF to give acrude product that was purified by Biotage eluting with 4/1-hexane/ethyl acetate to give 1.8 g of tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate as a solid.

tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)- 6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate MS (M + H)⁺ Calcd. 536.2 MS (M + H)⁺ Observ. 536.0 LC Condition Solvent A 100% Water - 0.1% TFA Solvent B 100% ACN - 0.1% TFA Start % B 2 Final % B 98 Gradient Time 1.6 min Stop Time 1.8 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN -H₂0 - 0.1% TFA Column Aquity UPLC BEH C18 1.7 um

Step 4: A solution of above tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (4 g) and HCl in dioxane (7.46 ml, 4M) was stirred for 4 hours. Concentration gave 3.58 g of 4-(4-(1-(4-chlorophenyl(cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid as a solid.

4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)- 1,3,5-triazin-2-ylamino)benzoic acid MS (M + H)⁺ Calcd. 480.1 MS (M + H)⁺ Observ. 480.1 LC Condition Solvent A 100% Water - 0.1% TFA Solvent B 100% ACN - 0.1% TFA Start % B 2 Final % B 98 Gradient Time 1.6 min Stop Time 1.8 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN -H₂0 - 0.1% TFA Column Aquity UPLC BEH C18 1.7 um

Preparation of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl chloride, In-02

A mixture of sulfuryl dichloride (1.68 g) and 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (0.40 g) in CH₂Cl₂ (4 mL) in sealed tube was heated at 106° C. for 16 hours. All the solvents were removed under vaccum to give crude 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl chloride (0.42 g) as yellow solid, which was used in the further reactions without purification.

Preparation of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy-D2)-1,3,5-triazin-2-ylamino)benzoic acid, In-03 and 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy-D2)-1,3,5-triazin-2-ylamino)benzoyl chloride, In-04

Step 1: iPr₂NEt (2.65 g) was added into the solution of 2,4,6-trichloro-1,3,5-triazine (3.78 g, 20.48 mmol) and 2,2,2-trifluoroethanol-D2 (2 g) in THF (150 mL). The reaction was stirred at room temperature for 16 hours.

Step 2: iPr₂NEt (2.65 g) and methyl 4-aminobenzoate (3.10 g) were added into the solution in step 1 and the reaction was stirred at room temperature for 16 hours. Solvents were removed under vaccum to give a residue, to which 20 ml of water and 100 ml of EtOAc were added. The resulted mixture was stirred t room temperature for 16 hours. The solid was isolated by filtration and dried under vaccum to give methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (7 g).

methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy- D2)-1,3,5-triazin-2-ylamino)benzoate MS (M + H)⁺ Calcd. 365.1 MS (M + H)⁺ Observ. 565.1 Retention Time 1.99 min LC Condition Solvent A 90% Water -10% Methanol-0.1% TFA Solvent B 10% Water -90% Methanol-0.1% TFA Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 5 mL/min Wavelength 220 Solvent Pair Water - Methanol- TFA Column PHENOMENEX-LUNA 4.6 × 50 mm S10

Step 3: iPr₂NEt (0.35 g) was added into the solution of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy-D2)-1,3,5-triazin-2-ylamino)benzoate (1 g) and 1-(4-chlorophenyl)cyclopropanamine (0.46 g) in THF (15 mL). The reaction was stirred at 70° C. for 16 hours. Solvents were removed under vaccum to give a residue, to which 100 ml of EtOAc were added. The organic phase was washed with water (2×20 mL) and brine (15 mL), dried over MgSO₄ and concentrated under vaccum to give methyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy-D2)-1,3,5-triazin-2-ylamino)benzoate (1.30 g) which was used in the further reaction without purification.

methyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6- (2,2,2-trifluoroethoxy-D2)-1,3,5-triazin-2-ylamino)benzoate MS (M + H)⁺ Calcd. 496.1 MS (M + H)⁺ Observ. 496.0 Retention Time 2.18 min LC Condition Solvent A 90% Water -10% Methanol-0.1% TFA Solvent B 10% Water -90% Methanol-0.1% TFA Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 5 mL/min Wavelength 220 Solvent Pair Water - Methanol- TFA Column PHENOMENEX-LUNA 4.6 × 50 mm S10

Step 4: The mixture of K₂CO₃ (0.84 g) and methyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy-D2)-1,3,5-triazin-2-ylamino)benzoate (0.75 g) in acetone (10 mL) and water (10 mL) in sealed tube was heated at 80° C. for 16 hours. After cooling, the mixture was added with 1N HCl to adjust pH to 2 when white solid formed. This white solid was isolated via filtration and dried to give compound In-03, 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy-D2)-1,3,5-triazin-2-ylamino)benzoic acid (0.75 g) which was used in the next step with purification.

4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy- D2)-1,3,5-triazin-2-ylamino)benzoic acid MS (M + H)⁺ Calcd. 482.1 MS (M + H)⁺ Observ. 482.3 Retention Time 2.55 min LC Condition Solvent A 5% ACN:95% Water: 10 mM Ammonium Actetate Solvent B 95% ACN:5% Water: 10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN:Water: Ammonium Actetate Column Phenomenex LUNA C18, 50 × 2, 3 u

Step 5: A mixture of sulfuryl dichloride (0.42 g) and 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy-D2)-1,3,5-triazin-2-ylamino)benzoic acid (0.31 g) in CH₂Cl₂ (2 mL) in sealed tube was heated at 90° C. for 16 hours. All the solvents were removed under vaccum to give crude compound In-04, 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy-D2)-1,3,5-triazin-2-ylamino)benzoyl chloride (0.31g) as yellow solid, which was used in the further reactions without purification.

Preparation of 4-(4-(benzyloxy)-6-(4-chlorobenzylamino)-1,3,5-triazin-2-ylamino)benzoic acid, In-05

Step 1: iPr₂NEt (50 mL) was added into the solution of 2,4,6-trichloro-1,3,5-triazine (10 g) and phenylmethanol (5.86 g) in THF (500 mL). The reaction was stirred at room temperature for 24 hours.

Step 2: Methyl 4-aminobenzoate (8.20 g) was added into the reaction mixture from Step 1 and the resulting mixture was stirred for 24 hours.

Step 3: (4-Chlorophenyl)methanamine (7.68 g) was added into the reaction mixture from Step 2. The reaction was carried out for another 24 hours. Then the reaction was quenched with saturated aqueous NaHCO₃ solution (200 mL). The aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layer was dried over MgSO₄ and concentrated under vaccum to offer crude methyl 4-(4-(benzyloxy)-6-(4-chlorobenzylamino)-1,3,5-triazin-2-ylamino)benzoate which was used in the further step without purification or purified by silica gel chromatography.

methyl 4-(4-(benzyloxy)-6-(4-chlorobenzylamino)- 1,3,5-triazin-2-ylamino)benzoate MS (M + H)⁺ Calcd. 476.1 MS (M + H)⁺ Observ. 476.1 Retention Time 2.17 min LC Condition Solvent A 5% ACN:95% Water: 10 mM Ammonium Actetate Solvent B 95% ACN:5% Water: 10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 5 mL/min Wavelength 220 Solvent Pair ACN:Water: Ammonium Actetate Column PHENOMENEX-LUNA 4.6 × 50 mm S10

Step 4: To a suspension of methyl 4-(4-(benzyloxy)-6-(4-chlorobenzylamino)-1,3,5-triazin-2-ylamino)benzoate (5 g) in acetone (150 mL) was added a solution of potassium carbonate (4.36 g) in water (80 mL). The mixture was heated to reflux for 48 hours. After cooling to room temperature, the reaction solution was acidified with 1N HCl to pH=3. The precipitate was collected by filtration and washed with water/acetone (5:1, 20 mL) and dried under vaccum to give 4-(4-(benzyloxy)-6-(4-chlorobenzylamino)-1,3,5-triazin-2-ylamino)benzoic acid (4.5 g)

4-(4-(benzyloxy)-6-(4-chlorobenzylamino)- 1,3,5-triazin-2-ylamino)benzoic acid MS (M + H)⁺ Calcd. 462.1 MS (M + H)⁺ Observ. 462.1 Retention Time 1.57 min LC Condition Solvent A 5% ACN:95% Water: 10 mM Ammonium Actetate Solvent B 95% ACN:5% Water: 10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair ACN:Water: Ammonium Actetate Column Phenomenex LUNA C18, 30 × 2, 3 u

Preparation of 3-(4-(benzyloxy)-6-(4-chlorobenzylamino)-1,3,5-triazin-2-ylamino)benzoic acid, In-06

Compound In-06, 3-(4-(benzyloxy)-6-(4-chlorobenzylamino)-1,3,5-triazin-2-ylamino)benzoic acid, was prepared via the same process to synthesize In-05, by using methyl 3-aminobenzoate.

4-(4-(benzyloxy)-6-(4-chlorobenzylamino)- 1,3,5-triazin-2-ylamino)benzoic acid MS (M + H)⁺ Calcd. 462.1 MS (M + H)⁺ Observ. 462.1 Retention Time 1.55 min LC Condition Solvent A 5% ACN:95% Water: 10 mM Ammonium Actetate Solvent B 95% ACN:5% Water: 10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair ACN:Water: Ammonium Actetate Column Phenomenex LUNA C18, 30 × 2, 3 u

Preparation of 4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid, In-07:

4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid was prepared via the same synthetic procedure of compound In-05, by using 2,2,2-trifluoroethanol.

4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)- 1,3,5-triazin-2-ylamino)benzoic acid MS (M + H)⁺ Calcd. 454.1 MS (M + H)⁺ Observ. 454.0 Retention Time 1.50 min LC Condition Solvent A 5% ACN:95% Water: 10 mM Ammonium Actetate Solvent B 95% ACN:5% Water: 10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 2 mL/min Wavelength 220 Solvent Pair ACN:Water: Ammonium Actetate Column Phenomenex LUNA C18, 30 × 2, 3 u

Preparation of 4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl chloride, In-08:

4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl chloride was prepared via the same synthetic procedure of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl chloride, In-02.

Syntheses of Claim I Synthesis of Compound 1001, 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)-1,4-diazepane-1-carboximidamide

iPr₂NEt (26 mg) was added into the solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl chloride (50 mg) and 1,4-diazepane-1-carboximidamide (15 mg) in THF (4 mL). The reaction was stirred at room temperature for 16 hours. Solvents were removed under vaccum to give a residue which was purified by preparative HPLC to give 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)-1,4-diazepane-1-carboximidamide (10 mg).

4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)- 6-(2,2,2-trifluoroethoxy)-1,3,5-triazin- 2-ylamino)benzoyl)-1,4-diazepane-1-carboximidamide MS (M + H)⁺ Calcd. 604.2 MS (M + H)⁺ Observ. 604.4 Retention Time 2.81 min LC Condition Solvent A 5% ACN:95% Water: 10 mM Ammonium Actetate Solvent B 95% ACN:5% Water: 10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN:Water: Ammonium Actetate Column Phenomenex LUNA C18, 50 × 2, 3 u

Synthesis of Compound 1002, (R)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-guanidinopentanoic acid

(R)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-guanidinopentanoic acid was prepared from 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl chloride and D-arginine by following the synthetic procedure of compound 1001.

(R)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)- 6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)- 5-guanidinopentanoic acid MS (M + H)⁺ Calcd. 636.2 MS (M + H)⁺ Observ. 636.4 Retention Time 2.47 min LC Condition Solvent A 5% ACN:95% Water: 10 mM Ammonium Actetate Solvent B 95% ACN:5% Water: 10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN:Water: Ammonium Actetate Column Phenomenex LUNA C18, 50 × 2, 3 u

Synthesis of Compound 1003, (S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-guanidinopentanoic acid

(S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-guanidinopentanoic acid was prepared from 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl chloride and L-arginine by following the synthetic procedure of compound 1001.

(S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)- 6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)- 5-guanidinopentanoic acid MS (M + H)⁺ Calcd. 636.2 MS (M + H)⁺ Observ. 636.4 Retention Time 2.43 min LC Condition Solvent A 5% ACN:95% Water: 10 mM Ammonium Actetate Solvent B 95% ACN:5% Water: 10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN:Water: Ammonium Actetate Column Phenomenex LUNA C18, 50 × 2, 3 u

Synthesis of Compound 1004, 4-(4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)-1,4-diazepane-1-carboximidamide

4-(4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)-1,4-diazepane-1-carboximidamide was prepared from 4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl chloride and 1,4-diazepane-1-carboximidamide by following the synthetic procedure of compound 1001.

4-(4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)- 1,3,5-triazin-2-ylamino)benzoyl)-1,4-diazepane-1-carboximidamide MS (M + H)⁺ Calcd. 578.2 MS (M + H)⁺ Observ. 578.3 Retention Time 1.57 min LC Condition Solvent A 5% ACN:95% Water: 10 mM Ammonium Actetate Solvent B 95% ACN:5% Water: 10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair ACN:Water: Ammonium Actetate Column Phenomenex LUNA C18, 30 × 2, 3 u

Synthesis of Compound 1005, 4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(4-guanidinobutyl)benzamide

4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(4-guanidinobutyl)benzamide was prepared from 4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl chloride and 1-(4-aminobutyl)guanidine by following the synthetic procedure of compound 1001.

4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)- 1,3,5-triazin-2-ylamino)-N-(4-guanidinobutyl)benzamide MS (M + H)⁺ Calcd. 566.2 MS (M + H)⁺ Observ. 566.3 Retention Time 1.55 min LC Condition Solvent A 5% ACN:95% Water: 10 mM Ammonium Actetate Solvent B 95% ACN:5% Water: 10 mM Ammonium Actetate Start % B 0 Final % B 100 Gradient Time 2 min Flow Rate 1 mL/min Wavelength 220 Solvent Pair ACN:Water: Ammonium Actetate Column Phenomenex LUNA C18, 30 × 2, 3 u

Synthesis of Compound 1006, (R)-2-(4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-guanidinopentanoic acid

To a solution of 4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (50 mg) in DMF (2 mL) was added CDI (35.7 mg). After stirring for 6 hours at room temperature, (S)-2-amino-5-guanidinopentanoic acid (38.4 mg) and DIPEA (0.03 8 mL) were added. The resulting mixture was stirred at room temperature for 16 hours and then heated at 50° C. for 24 hours. Solvents were removed under vaccum to give a residue which was purified by preparative HPLC to give (R)-2-(4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-guanidinopentanoic acid (2.2 mg).

(R)-2-(4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)- 1,3,5-triazin-2-ylamino)benzamido)-5-guanidinopentanoic acid MS (M + H)⁺ Calcd. 610.2 MS (M + H)⁺ Observ. 610.2 Retention Time 2.72 min LC Condition Solvent A 90% Water -10% Methanol-0.1% TFA Solvent B 10% Water -90% Methanol-0.1% TFA Start % B 0 Final % B 100 Gradient Time 4 min Flow Rate 5 mL/min Wavelength 220 Solvent Pair Water - Methanol- TFA Column PHENOMENEX-LUNA 3.0 × 50 mm S10

Synthesis of Compound 1007, (S)-2-(4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-guanidinopentanoic acid

(S)-2-(4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-guanidinopentanoic acid was prepared from 4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid and (S)-2-amino-5-guanidinopentanoic acid by following the synthetic procedure of compound 1006.

(S)-2-(4-(4-(4-chlorobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin- 2-ylamino)benzamido)-5-guanidinopentanoic acid MS (M + H)⁺ Calcd. 610.2 MS (M + H)⁺ Observ. 610.2 Retention Time 2.72 min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10% Water-90% Methanol-0.1% TFA Start % B  0 Final % B 100 Gradient Time 4 min Flow Rate 5 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFA Column PHENOMENEX-LUNA 3.0 × 50 mm S10

Synthesis of Compound 1008, N′-carbamoyl-4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)-N-cyclopentylpiperazine-1-carboximidamide and Compound 1009, 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)-N′-cyano-N-cyclopentylpiperazine-1-carboximidamide

To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (30 mg) and TBTU (17.15 mg) in DMF (3 mL) was added N′-cyano-N-cyclopentylpiperazine-1-carboximidamide hydrochloride (17.21 mg) and iPr₂NEt (0.039 mL). The reaction was stirred at room temperature for 4 hours. During HPLC purification using MeOH/THF buffter as eluting solvents, 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)-N′-cyano-N-cyclopentylpiperazine-1-carboximidamide partially hydrolyzed to N′-carbamoyl-4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)-N-cyclopentylpiperazine-1-carboximidamide. Then the mixture was repurified by prep HPLC (ACN/amonium acetate buffter) to give N′-carbamoyl-4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)-N-cyclopentylpiperazine-1-carboximidamide (4.7 mg) and 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)-N′-cyano-N-cyclopentylpiperazine-1-carboximidamide (6.3 mg).

N′-carbamoyl-4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2- trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)-N- cyclopentylpiperazine-1-carboximidamide MS (M + H)⁺ Calcd. 701.3 MS (M + H)⁺ Observ. 701.4 Retention Time 2.33 min LC Condition Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B  30 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN:Water:Ammonium Actetate Column Phenomenex LUNA C18, 50 × 2, 3u

4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)- 1,3,5-triazin-2-ylamino)benzoyl)-N′-cyano-N-cyclopentylpiperazine- 1-carboximidamide MS (M + H)⁺ Calcd. 683.3 MS (M + H)⁺ Observ. 683.4 Retention Time 2.39 min LC Condition Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B  30 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN:Water:Ammonium Actetate Column Phenomenex LUNA C18, 50 × 2, 3u

Synthesis of Compound 1010, 1-(azetidin-1-yl(4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)piperazin-1-yl)methylene)urea and Compound 1011, N-(azetidin-1-yl(4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)piperazin-1-yl)methylene)cyanamide

Compound 1010, 1-(azetidin-1-yl(4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)piperazin-1-yl)methylene)urea and Compound 1011, N-(azetidin-1-yl(4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)piperazin-1-yl)methylene)cyanamide were prepared by the same synthetic procedure towards Compound 1008 and Compound 1009 by using N-(azetidin-1-yl(piperazin-1-yl)methylene)cyanamide hydrochloride.

1-(azetidin-1-yl(4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)- 6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)piperazin- 1-yl)methylene)urea MS (M + H)⁺ Calcd. 673.2 MS (M + H)⁺ Observ. 673.4 Retention Time 2.03 min LC Condition Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B  30 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN:Water:Ammonium Actetate Column Phenomenex LUNA C18, 50 × 2, 3u

N-(azetidin-1-yl(4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6- (2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)piperazin- 1-yl)methylene)cyanamide MS (M + H)⁺ Calcd. 655.2 MS (M + H)⁺ Observ. 655.4 Retention Time 2.13 min LC Condition Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B  30 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN:Water:Ammonium Actetate Column Phenomenex LUNA C18, 50 × 2, 3u

Synthesis of Compound 1012, 1-04-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)piperazin-1-yl)(piperidin-1-yl)methylene)urea and Compound 1013, N-((4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)piperazin-1-yl)(piperidin-1-yl)methylene)cyanamide

Compound 1012, 1-((4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)piperazin-1-yl)(piperidin-1-yl)methylene)urea and Compound 1013, N-((4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)piperazin-1-yl)(piperidin-1-yl)methylene)cyanamide were prepared by the same synthetic procedure towards Compound 1008 and Compound 1009 by using N-(piperazin-1-yl(piperidin-1-yl)methylene)cyanamide hydrochloride.

1-((4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2- trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)piperazin- 1-yl)(piperidin-1-yl)methylene)urea MS (M + H)⁺ Calcd. 701.3 MS (M + H)⁺ Observ. 701.4 Retention Time 2.22 min LC Condition Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B  30 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN:Water:Ammonium Actetate Column Phenomenex LUNA C18, 50 × 2, 3u

N-((4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2- trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoyl)piperazin-1- yl)(piperidin-1-yl)methylene)cyanamide MS (M + H)⁺ Calcd. 683.3 MS (M + H)⁺ Observ. 683.4 Retention Time 2.40 min LC Condition Solvent A 5% ACN:95% Water:10 mM Ammonium Actetate Solvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B  30 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair ACN:Water:Ammonium Actetate Column Phenomenex LUNA C18, 50 × 2, 3u

Synthesis of Compound 1014, (4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)phenyl)(2-iminoimidazolidin-1-yl)methanone

To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (100 mg) and TBTU (73.6 mg) in DMF (2 mL) was added 2-(2-aminoethyl)-1,3-di-Boc-guanidine (63.0 mg) and iPr₂NEt (0.146 mL). After stirring at room temperature for 3 hours, the mixture was purified by preparative HPLC to give (4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)phenyl)(2-iminoimidazolidin-1-yl)methanone (10.8 mg).

(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)- 1,3,5-triazin-2-ylamino)phenyl)(2-iminoimidazolidin-1-yl)methanone MS (M + H)⁺ Calcd. 547.2 MS (M + H)⁺ Observ. 574.0 Retention Time 3.10 min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10% Water-90% Methanol-0.1% TFA Start % B  30 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFA Column PHENOMENEX-LUNA 2.0 × 50 mm 3 um

Synthesis of Compound 1015, (S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-guanidinopropanoic acid

To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (100 mg) and TBTU (73.6 mg) in DMF (2 mL) was added (S)-2-amino-3-guanidinopropanoic acid hydrochloride (41.9 mg) and iPr₂NEt (0.146 mL). After stirring at room temperature for 3 hours, the mixture was purified by preparative HPLC to give (S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-guanidinopropanoic acid (35 mg).

(S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2- trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)- 3-guanidinopropanoic acid MS (M + H)⁺ Calcd. 608.2 MS (M + H)⁺ Observ. 608.0 Retention Time 2.11 min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10% Water-90% Methanol-0.1% TFA Start % B  50 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFA Column PHENOMENEX-LUNA 2.0 × 50 mm 3 um

Synthesis of Compound 1016, (S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-guanidinopropanoic acid

To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (100 mg) and TBTU (73.6 mg) in DMF (5 mL) was added (S)-2-amino-5-guanidinopentanamide dihydrochloride (51.3 mg) and iPr₂NEt (0.146 mL). After stirring at room temperature for 3 hours, the mixture was purified by preparative HPLC to give (S)—N-(1-amino-5-guanidino-1-oxopentan-2-yl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide (100 mg).

(S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2- trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3- guanidinopropanoic acid MS (M + H)⁺ Calcd. 635.2 MS (M + H)⁺ Observ. 635.1 Retention Time 1.98 min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10% Water-90% Methanol-0.1% TFA Start % B  50 Final % B 100 Gradient Time 4 min Flow Rate 0.8 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFA Column PHENOMENEX-LUNA 2.0 × 50 mm 3 um

Syntheses of Compounds 1017-1027

The general procedures below pertain to the experimental procedures. 4-(4- or 3-(benzyloxy)-6-(4-chlorobenzylamino)-1,3,5-triazin-2-ylamino)benzoic acid (0.121 mmol, 1 eq.) in DMF (1.2 mL) was added into a Wheaton tube (16×100 mm) which contained amine(0.182 mmol, 1.5 eq.) and followed by adding HATU (0.182 mmol, 1.5 eq.) and DIPEA (0.364 mmo, 3 eq.). The tubes were capped and shaken overnight at room temperature. All products were purified by preparation HPLC.

HPLC purity was determined using a Polymer Lab 2100 ELS detector (Evap. Temp.=45° C., Neb. Temp.=35° C.) Waters ZQ with ESCi mass spectrometer. A=5:95 ACN:Water; B=95:5 ACN:Water; Modifier=10 mM NH₄OAc. Retention time was recorded in minutes.

Analytical Method A

Column Waters Xbridge 4.6 × 100 mm 5 um C18 Time B % Flow 0.00 10 2.00 6.00 95 2.00 7.50 95 2.00 8.00 10 2.00 10.00 10 3.00

Analytical Method B

Column Supelco Ascentis Express 4.5 × 50 mm 3 um C18 Time B % Flow 0.00 5.0 2.0 8.00 95 2.0 9.00 95 2.0 9.01 5.0 2.0 10.00 5.0 2.0

Compd HPLC Calcd. Obs. HPLC Structure # Rt MS Ion MS Ion Method

1017 4.71 586.2 586.4 A

1018 4.74 586.2 586.4 A

1019 4.09 746.3 746.4 A

1020 4.7  518.2 518.3 B

1021 4.72 518.2 518.3 B

1022 5.13 658.2 658.5 B

1023 5.4  658.2 658.4 B

1024 4.88 574.2 574.4 B

1025 4.9  574.2 574.4 B

1026 4.71 572.2 572.4 B

1027 4.72 572.2 572.4 B

Syntheses of Compounds 1028-1031

General Procedure:

A stock solution of the 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (626.6 mgs, 1.30 mmols) and HATU (494 mgs, 1.30 mmols) in DMF (6.5 mL) was prepared. The mixture was allowed to stir at room temp for 10 minutes. A stock solution of iPr₂NEt (676 μLs, 3.9 mmols) in DMF (6.0 mL) was prepared. To each 16×100 mm Wheaton vial containing the peptide reagents was added 0.5 mL of the iPr₂NEt solution, followed by 0.5 mL of the 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid/HATU solution. Vials were covered and allowed to shake at room temp for 18 hours. Contents were transferred to 96 well 25 μm filter plate collecting into a 96 well deep-well plate. Each vial was rinsed with 500 μL of MeOH and the solution was transferred to the appropriate wells of the filter plate. The mixtures were purified by preparative HPLC.

Initial Analysis:

WFD-446-UPLC4:

-   -   MassLynx 4.1     -   Waters 2777 Sample Manager (CTC MXY01-01B)     -   Waters Acquity Binary UPLC pump     -   Waters Acquity TUV detector (220 nm)     -   Waters SD mass spectrometer with ESI probe

Column-Waters Xbridge 2.1×50 mm 1.7 um C18 (BEH-C18 for UPLC) Mobile Phase-A=5:95 SS:Water; B=95:5 SS:Water; Modifier=10 mM NH₄OAc

Methods

WFD-UPLC-001 MeOH (2×50 mm, 1.7 um, 5 min):

Time B % Flow 0.00′ 0 0.5 4.00′ 100 0.5 5.00′ 100 0.5 5.10′ 0 0.5 5.50′ 0 0.5

WFD-UPLC-002 ACN (2×50 mm, 1.7 um, 5 min):

Time B % Flow 0.00′ 0 0.83 4.00′ 100 0.83 5.00′ 100 0.83 5.10′ 0 0.83 5.50′ 0 0.83

Preparation

WFD-445-PMS3 (Dionex APS-3000):

-   -   Chromeleon 6.70 sp1 LC software     -   Dionex P680 binary pump for analytical     -   Dionex PP 150 binary pump prep     -   Dionex UVD340U UV spectrometer (220 nm)     -   Sedex 75 ELS detector     -   Thermo-Finnigen MSQ Surveyor Plus mass spectrometer     -   Column-Waters Xbridge 19×150 mm 5 um C18     -   Guard Column-Waters Xbridge 19×10 mm 5 um C18     -   Mobile Phase—A=Water; B=95:5 MeOH; Water; Modifier=20 mM NH₄OAc

Method

-   -   WFD-PMS3_Methanol (19×150 mm): 30 mL/min, 0′=40% B, 0.5′ (10         mL/min)=40% B, 2′ (10 mL/min)=40% B, 2.5′ (20 mL/min)=30% B,         20′=95% B, 20′=95% B     -   Sample Drying—GeneVac Program HT-24-ACN-H2O-Buffer in 16×100 TT         & AL blocks: Temp=45 C., 0.3 h @ 175 to 40 bar, 1.7 h @ 40 bar,         defrost, 6 h @ 8 bar, 6 h @ Full Vac, defrost.

Final Analysis

WFD-446-LCMS2:

-   -   MassLynx 4.0 SP4 LC-MS software     -   CTC-Leap HTS-PAL autosampler     -   Agilent 1100 binary pump     -   Agilent 1100 photodiode array (220 nm)     -   Polymer Lab 2100 ELS detector (Evap. Temp.=45° C., Neb.         Temp.=35° C.)     -   Waters ZQ mass spectrometer     -   Column-Supelco Ascentis Express 4.6×50 mm 2.7 um C18     -   Mobile Phase—A=5:95 ACN:Water; B=95:5 ACN:Water; Modifier=10 mM         NH₄OAc

Method

WFD-MUX-004 (4.6×50 mm):

Time B % Flow 0.00′ 0 2.0 8.00′ 100 2.0 9.00′ 100 2.0 9.10′ 100 2.0 10.00′ 0 2.0

Cmpd. HPLC Calcd. Obs. Structure No. Rt MS Ion MS Ion

1028 4.31 637.2 637.4

1029 3.97 785.3 785.5

1030 4.42 694.3 694.4

1031 4.29 751.3 751.5

Biological Methods

Infection assays. HCV pseudoparticles, produced using standardized methodology (Bartosch, B., Dubuisson, J. and Cosset, F.-L. J. Exp. Med. 2003, 197:633-642) were made via a liposome-based transfection procedure of 293T cells with plasmids expressing the murine leukemia virus capsid and polymerase proteins, an MLV genome encoding the luciferase reporter gene, and envelope glycoproteins from either HCV or vesicular stomatitis virus (VSV). The genotype 1a HCV E1 and E2 envelope coding sequences were derived from the H77C isolate (GenBank accession number AF009606). Media containing pseudoparticles was collected 3 days following transfection, filtered, and stored at −20° C. as a viral stock. Infections were performed in 384-well plates by mixing pseudovirus with 1×10⁴ Huh7 cells/well in the presence or absence of test inhibitors, followed by incubation at 37° C. Luciferase activity, reflecting the degree of entry of the pseudoparticles into host cells, was measured 2 days after infection. The specificity of the compounds for inhibiting HCV was determined by evaluating inhibition of VSV pseudoparticle infection.

Compounds and data analysis. Test compounds were serially diluted 3-fold in dimethyl sulfoxide (DMSO) to give a final concentration range in the assay of 50.0 μM to 0.04 pM. Maximum activity (100% of control) and background were derived from control wells containing DMSO but no inhibitor or from uninfected wells, respectively. The individual signals in each of the compound test wells were then divided by the averaged control values after background subtraction and multiplied by 100% to determine percent activity. Assays were performed in duplicate and average EC₅₀ values (reflecting the concentration at which 50% inhibition of virus replication was achieved) were calculated. Compound EC₅₀ data is expressed as A=0.01≦10 nM; B=10-1000 nM; C≧1000 nM. Representative data for compounds are reported in Table 2.

TABLE 2 Compd EC₅₀ EC₅₀ # Structure (1a, nM) (1a, nM) 1001

A 1002

A 1003

  0.711 A 1004

B 1005

 29.480 B 1006

B 1007

B 1008

A 1009

  3.569 A 1010

A 1011

A 1012

A 1013

A 1014

  3.010 A 1015

A 1016

  0.352 A 1017

B 1018

B 1019

B 1020

 174.600 B 1021

C 1022

 62.510 B 1023

B 1024

B 1025

4479.000 C 1026

B 1027

B 1028

A 1029

A 1030

A 1031

A

It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. 

What is claimed is:
 1. A compound of Formula I, including pharmaceutically acceptable salts thereof:

wherein a, b and c are each nitrogen; or a and b are each nitrogen, while c is —CH; or b and c are each nitrogen, while a is —CH; or a and c are each nitrogen, while b is —CH; R¹ is selected from alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, and benzyl, wherein the benzyl moiety is substituted with 0-3 substituents selected from halo, alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, cyano, haloalkyl, alkoxy, and haloalkoxy; R² is selected from alkyl, cycloalkyl, ((Ar¹)alkyl, (Ar¹)cycloalkyl, ((Ar¹)cycloalkyl)alkyl, ((Ar¹)alkyl)cycloalkyl, and (((Ar¹)alkyl)cycloalkyl)alkyl; Ar¹ is phenyl substituted with 0-3 substituents selected from halo, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, and haloalkoxy; R³ is hydrogen, alkyl or cycloalkyl; R⁴ is selected from hydrogen, halogen, alkyl, alkoxyl, alkylamino and alkylthio; or R² and R⁴ can be connected by a carbon, oxygen, nitrogen or sulfur atom to form a ring; Y is

X is selected from O, NR¹¹, CO, CONR¹¹, NR¹¹NR¹² and CONR¹¹NR¹²; R¹¹ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, and benzyl, wherein the benzyl moiety is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; R¹² is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, and benzyl, wherein the benzyl moiety is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; R⁵ is selected from alkyl, cycloalkyl, (cycloalkyl)alkyl, (alkyl)cycloalkyl, ((alkyl))cycloalkyl)alkyl, a bridged bicycloalkyl, a fused bicycloalkyl, and a spiro bicycloalkyl, and is substituted with 0-4 substituents selected from the group of halo, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO₂R¹³, CON(R¹⁴)(R¹⁵), N(R¹⁴)(R¹⁵), tetrahydrofuranyl, tetrahydropyranyl, and Ar²; or R⁵ is Ar³; R¹³ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, ((hydroxyalkyl)alkoxy)alkoxy, and ((alkoxy)alkoxy)alkoxy; R¹⁴ is selected from hydrogen, alkyl, cycloalkyl, alkylcarbonyl, and alkoxycarbonyl, which is substituted with 0-4 substituents selected from the group of halo, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO₂R²¹, CON(R²²)(R²³), and N(R²²)(R²³); R¹⁵ is hydrogen or alkyl; or R¹⁴ and R¹⁵ taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-2 substituents selected from alkyl, alkylcarbonyl, and alkoxycarbonyl; R²¹ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, ((hydroxyalkyl)alkoxy)alkoxy, and ((alkoxy)alkoxy)alkoxy; R²² is selected from hydrogen, alkyl, cycloalkyl, alkylcarbonyl, and alkoxycarbonyl, which is substituted with 0-4 substituents selected from the group of halo, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, ester, amido, and amino; R²³ is hydrogen or alkyl; or R²² and R²³ taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-2 substituents selected from alkyl, alkylcarbonyl, and alkoxycarbonyl; Ar² is selected from phenyl, indanyl, tetrahydronaphthyl, isochromanyl, benzodioxolyl, pyridinyl, pyrazolyl, imidazolyl, and triazolyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkyenyl, haloalkyl, alkoxy, haloalkoxy, N(R¹⁶)(R¹⁷), and alkylCO; R¹⁶ is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, or alkoxycarbonyl; R¹⁷ is hydrogen or alkyl; or R¹⁶ and R¹⁷ taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-2 substituents selected from alkyl, alkylcarbonyl, and alkoxycarbonyl; Ar³ is selected from phenyl, indanyl, fluorenyl, biphenyl, terphenyl, pyridinyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, benzoxazolyl, indolinyl, and dibenzofuranyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkenyl, haloalkyl, cycloalkyl, (CO₂R¹³)alkyl, (CO₂R¹³)alkenyl, (CON(R¹⁶)(R¹⁷))alkyl, phenyl, hydroxyl, alkoxy, haloalkoxy, alkylcarbonyl, CO₂R¹³, CON(R¹⁶)(R¹⁷), and PhCONHSO₂; or Ar³ is phenyl substituted with 1 substituent selected from benzyl, tetrazolyloxy, thiazolyl, phenylpyrazolyl, methyloxadiazolyl, thiadiazolyl, triazolyl, methyltriazolyl, tetrazolyl, pyridinyl, and dimethoxypyrimdinyl; R⁶ is hydrogen, alkyl, cycloalkyl, CN or CON(R¹⁶)(R¹⁷); R⁷ is hydrogen, alkyl, cycloalkyl, CN or CON(R¹⁶)(R¹⁷); R⁸ is hydrogen, alkyl, cycloalkyl, CN or CON(R¹⁶)(R¹⁷); R⁹ is hydrogen, alkyl, cycloalkyl, CN or CON(R¹⁶)(R¹⁷); or R⁶ and R⁷ can be connected by a carbon, oxygen, nitrogen or sulfur atom to form a ring; or R⁶ and R⁸ can be connected by a carbon, oxygen, nitrogen or sulfur atom to form a ring; or R⁷ and R⁸ can be connected by a carbon, oxygen, nitrogen or sulfur atom to form a ring; or R⁸ and R⁹ can be connected by a carbon, oxygen, nitrogen or sulfur atom to form a ring; or R⁶ and R¹¹ can be connected by a carbon, oxygen, nitrogen or sulfur atom to form a ring; or R⁷ and R¹¹ can be connected by a carbon, oxygen, nitrogen or sulfur atom to form a ring; or R⁸ and R¹¹ can be connected by a carbon, oxygen, nitrogen or sulfur atom to form a ring.
 2. A compound, including pharmaceutically acceptable salts thereof, which is selected from the group of:


3. A compound, including pharmaceutically acceptable salts thereof, which is selected from the group of:


4. A composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier.
 5. A composition comprising a compound of claim 2, and a pharmaceutically acceptable carrier.
 6. A composition comprising a compound of claim 3, and a pharmaceutically acceptable carrier.
 7. The composition of claim 4 further comprising at least one additional compound having therapeutic benefits for HCV wherein the compound is selected from the group of interferons, cyclosporins, interleukins, HCV metalloprotease inhibitors, HCV serine protease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors, HCV NS4B protein inhibitors, HCV entry inhibitors, HCV assembly inhibitors, HCV egress inhibitors, HCV NS5A protein inhibitors, HCV NS5B protein inhibitors, and HCV replicon inhibitors.
 8. A method of treating hepatitis C infection comprising administering a therapeutically effective amount of a compound of claim 1 to a patient.
 9. The method of claim 8 further comprising administering at least one additional compound having therapeutic benefits for HCV wherein the compound is selected from the group of interferons, cyclosporins, interleukins, HCV metalloprotease inhibitors, HCV serine protease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors, HCV NS4B protein inhibitors, HCV entry inhibitors, HCV assembly inhibitors, HCV egress inhibitors, HCV NS5A protein inhibitors, HCV NS5B protein inhibitors, and HCV replicon inhibitors. 